Dysfunction of striated muscle underlies both cardiac failure and overall frailty in the elderly. The mortality and economic burden to society arising from the age-associated dysfunction of striated muscle is enormous. Cost estimates of $80 billion a year and a doubling time of forty years are the direct result of the changing demographics of the US population, with a substantial decrease in the proportion of the US population in the 25-45 age group and an increase in the 55-100 age group. The overall working hypothesis of this proposal is that genetic modification of the heart and skeletal muscles provides a potential intervention to prevent, halt or reverse age-associated decrements in striated muscle function in vivo. The shared group goals of the project are: 1) To develop gene transfer and genetic model technologies for the study of the structure-function relationships in heart and skeletal muscles of young and old mice, rats, and Drosophila melanogaster in vivo. 2) To use gene transfer and genetic model technologies to identify and modify specific molecular targets in the sarcomere and cytoskeleton for enhancing or restoring normal functionality of heart and skeletal muscles of young and old; mutant, transgenic and wild type; mice, rats, and Drosophila in vivo. 3) To understand how disease-causing mutations in cytoskeletal proteins lead to progressive, age- related alterations in heart and skeletal muscle function using cell culture and invertebrate (Drosophila) and vertebrate (rodent) model systems in vivo. The contribution of the "fly model" to our understanding of the genetic basis of development and of aging has been remarkable, yet little is known of the age-associated changes in the function of the heart. With short experimental turn-around times for studies of the interaction of genetic modifications and aging of striated muscle (Project 3), the "fly model" provides a powerful interface with the companion studies of genetic modification and aging in dystrophic, transgenic and wild type mice (Projects 1 &2). The three projects with the assistance of the capabilities of the Functionality Core enable the Program Project to focus on an understanding of mechanisms underlying the structure-function relationships of progressive age-related dysfunction and its remediation through genetic modification in mutant, transgenic, and wild type rodents and Drosophila in vivo.